NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Lung cancer is the leading cause of cancer-related death in the U.S. and will soon reach epidemic levels worldwide. Mortality from this disease could be reduced through the identification of high-risk individuals and the implementation of effective therapies to prevent recurrence of lung cancer after tumor resection. Our studies have identified genes inactivated by aberrant CpG island methylation as candidate biomarkers for early detection of lung cancer. The parent grant to this competitive supplement, "Biomarkers to Assess Selenium Chemoprevention for NSCLC," is focused on determining the ability of a panel of genes inactivated through gene promoter methylation in sputum or plasma to predict response to therapy and the recurrence of cancer for resected Stage I lung cancer patients participating in a Phase III Chemoprevention trial evaluating L- selenomethionine. The studies proposed in this competitive supplement will complement and extend the work in the parent grant in several ways. Gene promoter hypermethylation has emerged as a major mechanism in the initiation and development of cancer and its reversal by pharmacological agents may offer an effective strategy for primary and adjuvant (secondary prevention) cancer therapy. Epigenetic therapy through combining a demethylating agent such as 5-azacytidine and an inhibitor of histone deacetylase (e.g., MS275) is now approved by the FDA for treatment of myelodysplastic syndrome and acute leukemia. Most important, exciting responses are being seen in a Phase I/II clinical trial for advanced lung cancer. Studies in this competitive supplement will use a validated orthotopic nude rat lung cancer model to define the efficacy of epigenetic therapy for affecting growth of tumors with specific oncogenic mutations and harboring hundreds of methylated genes. Methylation and expression arrays on treated and vehicle tumors will identify biomarkers (genes demethylated and re-expressed) that could ultimately be used in human trials to predict responders to adjuvant and primary epigenetic therapy for lung cancer. These studies will also define whether a key mechanism for the efficacy of epigenetic therapy is targeting and removal of self-renewing tumor cells. Finally, we will address whether combining epigenetic therapy with standard-of-care cytotoxic therapy (platinum- based) can further impact tumor growth. PUBLIC HEALTH RELEVANCE: These studies will use a validated orthotopic nude rat lung cancer model to define the efficacy of epigenetic therapy for affecting growth of lung tumors with specific oncogenic mutations and harboring hundreds of methylated genes. Methylation and expression arrays on treated and vehicle tumors will identify biomarkers (genes demethylated and re-expressed) that could ultimately be used in human trials to predict responders to adjuvant and primary epigenetic therapy for lung cancer. Studies in this application could bring epigenetic therapy closer to the forefront of managing the most devastating form of cancer by providing key new insights to guide and further the development of human clinical trials for treatment and prevention of lung cancer.